The proposed MDRC brings together experienced and talented investigators, unique resources, and innovative techniques to develop medications for the treatment of cocaine and heroin abuse. Existing medications, primarily to treat heroin addiction, all have serious flaws. A major theme of this Center is that the addict population is heterogeneous and effective medications will most likely emerge for subgroups rather than as universal antidotes. The second major theme is the search for better methods to identify these subgroups and to screen possible medications for effectiveness prior to instituting large scale clinical trials. We will use tools as diverse as improved psychiatric screening, cue reactivity paradigms, laboratory self-administration protocols, brain imaging techniques, and staggered clinical trials. The proposed Center consists of 3 projects. Project I will develop a smoked heroin paradigm and then use it in the Residential Laboratory to evaluate both new medications for opiate addiction, e.g., depot naltrexone and methoclocinnamox, as well as improving outcome and acceptability of existing medications such as methadone and naltrexone. Project 2 will use an improved SPECT imaging technique to demonstrate the correlation between regional brain activation and different phases of cocaine withdrawal, developing markers for evaluating new medications. A promising medication, whether to treat withdrawal, craving, or act as a blocker, could be studied for its effect on the relevant brain markers. The quantitative nature of the findings could cut through the thicket of variables that confound integration of controlled clinical trials. In keeping with the theme of targeting subgroups, Projects 3 will evaluate treatment seeking cocaine (3) abusers and then use existing psychiatric medications to see whether treating specific disorders such as depression or anxiety will improve outcome and retention. Project 3, in addition, will use both a cue reaction paradigm and a novel clinical trial design to pilot test new medications for cocaine treatment. Overall, the Center has the potential to become an important resource in the search for better medications for heroin and cocaine abuse that will improve our treatment capability.